The overall goal of this proposal is to understand the mechanism of blood cell transformation during leukemogenesis. Chromosomal translocations are frequently involved in the process of leukemia development. Among various translocations, t(8;21)(q22;q22) is reported in 8-20% cases of acute myeloid leukemia (AML) depending on the genetic background and geographic locations of the population, which makes it one of the most common translocations associated with AML. This translocation leads to the fusion of the AML1 and ETO genes and generates various forms of AML1-ETO fusion proteins. In the previous funding period, we discovered that additional mutations, such as abnormal hematopoietic growth factor signal transduction due to loss of one of the human sex chromosomes or deletion or mutation of the NHR4 zinc finger domain of AML1- ETO, cooperate with t(8;21) in AML development. Furthermore, we identified a DNA and RNA binding domain containing protein called SON that specifically interacts with the NHR4 zinc finger domain of ETO. In the current funding period, we propose to test the hypotheses that disrupting IL-3 and/or GM-CSF signal transduction is a major additional mutation associated with loss of one human sex chromosome in t(8;21) leukemia development and that SON is a critical factor in hematopoietic cells. The studies proposed in Specific Aim 1 will define the role of IL3 and GM-CSF receptor signal transduction in the development of t(8;21) related leukemia. The studies proposed in Specific Aim 2 will characterize the role of SON in AML1-ETO involved leukemogenesis. The studies proposed in Specific Aim 3 will analyze the biological function of SON in hematopoiesis. These studies will address important questions about hematopoiesis and leukemogenesis, which may provide valuable insight into the treatment of leukemia and other cancers.